Syndrome of the Month

332332~~~~~~~~~~~~~~~~~~~~~~~~~~~~~J7Med Genet 1992; 29: 332-337

SYNDROME OF THE MONTH

W.eaver syndrome

T R P Cole, N R Dennis, H E Hughes

In 1974 Weaver et al' described two unrelated born at 40 to 41 weeks' gestation. Cases 1, 2, children with accelerated growth, advanced and 3 were born by caesarean section because bone age, and a characteristic facial appearance. of fetal distress, but there were no serious The condition subsequently became known as neonatal complications. Paternal ages were 33, the Weaver-Smith syndrome (WSS). Since the 26, 35, and 32 years and maternal ages 39, 25, original report, approximately 30 further cases 28, and 23 years, respectively. have been described. It is still debatable if the syndromes of Marshall-Smith (MSS) and Weaver-Smith (WSS) are on24or separate Review of clinical features entities,516 but at present most authors believe GROWTH they are different conditions.' Here we briefly In WSS there is increased prenatal (table 2) include details on four new cases of Weaver- and postnatal weight (fig 3). Birth length and Smith syndrome and review the published OFC seem to be similarly affected (figs 4 and reports. 5), but there are fewer data on these particular parameters. On reviewing 25 published cases 1 -8and the four new cases in this Case reports (figs 1-6) report, birth length and OFC are increased Clinical details of four new cases of WSS are above the 97th centile in 15/18 and 8/15 chil- summarised in table 1. All are male and were dren, respectively. Postnatal height and OFC

(c)

Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF4 4XW. T R P Cole H E Hughes Wessex Regional Genetic Service, The Pr'incess Anne Hospital, Southampton S09 4HA. N R Dennis CorrespondenceCorrspodenctotoDrDr Cole.Cle.Figure 1 Case 1 at ages (a) 4 months, (b) 12 months, (c and d) 5 years. Weaver syndrome 333 (a)

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w ~ ~~~~~_ . ,-'' _~.r" ,

(b)

(d)

Kg lb cm in Boys' weight 190 190 Boys' height 80 0 170 170 ,' / 70 )_ ~~~~~~~~~~~//150 60 130 iO 50 // 110 40 0~~~~~~~~ 90 1104 < II|I0 I I,,/I, O 30 70

20 50 30 10 10 2 50 L I 6 1 3 5 7 9 11 13 15 17 19 130 5 7 9 11 13 15 17 19 Age (years) Age (years) Figure 3 Weight chart cases 1-4. Figure 4 Height chart cases 1-4. 334 Cole, Dennis, Hughes

cm CRANIOFACIAL FEATURES (TABLE 1) In infancy the face is round with retrognathia 62 Mean (50th centile) - and a small but very prominent chin, which 58 S often has a central dimple (figs 1 and 2). In +2SD (98th centile) °i childhood, the face becomes longer and less 54 distinctive,'8 although the latter may reflect with 50 - 0- - lack of experience in assessing patients - 0 * WSS in older age groups. In mid-childhood 46 ,-- there are similarities between the facial gestalt / .-.fl717 of Sotos syndrome and WSS (figs Id and 2c). 42 Cases 1, 2, and 4 in the present series were having Sotos syndrome. 38 initially diagnosed as 34 LIMB AND SKELETAL ANOMALIES In I -_-1 _v 1 3 5 7 912 15 18 2 4 6 81014 18 In the two original cases,' prominent fingertip (.u- Months - -!-- Years - ( pads (fig 6) and deep set nails were described. These features can also be seen on examination Figure 5 Occipitofrontal circumference charts cases of the toes (fig 6). Camptodactyly, although 1-4. common (11/16, Ardinger et al7) is by no means a consistent finding and was seen in only one of the four present cases. Cases 1, 2, and 3 had a typical pattern of overriding toes (fig 6) which also appear to be increased (usually >97th required surgical correction in case 2. This centile), but in the authors' own experience, feature may just reflect crowding of the toes, which is in keeping with the findings of but could be analogous to the camptodactyly Majewski et al,9 it seems that weight is more seen in the hands. Similar toe abnormalities significantly increased than height (figs 3 and have been identified in previous case re- 4). The overgrowth in the cases of Bosch- ports'247 '20 in addition to a variety of foot Banyeras et al2 and Weisswichert et all2 was deformities, such as pes cavus'5 and club feet.7 less dramatic, but both children had cardiac Knee and elbow joints are often rather large lesions. Unlike Sotos syndrome, the most with limitation of extension. Radiological ex- commonly differentiated overgrowth con- amination of these joints may show metaphy- dition, OFC in WSS does not appear to be seal flaring. > 97th centile in all cases. Five patients out of 29 have post-infancy OFC values between the 50th and 97th centiles. BEHAVIOUR AND DEVELOPMENT The growth pattern in adolescence and It is likely that there has been ascertainment through to adulthood has not yet been defined, bias towards the severe end of the develop- but the adult cases reported to date have mental spectrum in the early descriptions. All achieved heights of 209-5 cm (+ 5 2 SD),7 seven cases of WSS reported by Ardinger et al7 187 cm (+ 3.5 SD),'8 and 161 cm (50th were developmentally delayed on early assess- centile).'6 However, the diagnosis of WSS in ments, although one patient subsequently the latter case cannot be confirmed on the achieved an IQ score of 100 and one other information provided. These limited data patient was described as being within the low would seem to suggest that adult height in average range. Cases 1 and 2 of the present WSS may be greatly increased; however, these series fall into the category of borderline or reported cases were diagnosed as adults when mild mental handicap and together with case 4 tall stature may have biased ascertainment. show marked early motor and speech delay.

Figure 6 Case I showing prominent finger tip pads, prominent pads on toes, and overriding 4th toe. Weaver syndrome 335

Table 1 Clinical summary: four new cases of Weaver-Smith syndrome There are suggestions in published case re- Case 1 Case 2 Case 3 Case 4 Ref 7 ports that muscle tone may increase with time. In the series of patients reported by Ardinger Age 4y Ilm 5y Im 7m ly 1Om Birth weight (g) 5500 4200 4500 4200 et al,7 those patients with hypotonia were aged (SD) (+3-8) (+1-3) (+2 3) (+1-3) 0 to 24 months while the hypertonic patients Birth length (cm) 61 56-6 (SD) (+5-7) (+3-4) were aged between 5 and 39 years. Lower limb Birth OFC (cm) 39 38 reflexes in cases 2, 3, and 4 of the current (SD) (+1-5) (+ 1-0) Broad forehead + + + + 18/19 report are rather brisk, although the plantar Round face in + + + + response is still flexor. Case 7 described by infancy Micrognathia + + + + 17/19 Ardinger et al' had a progressive spasticity Prominent philtrum + + + + 10/14 resulting in the patient becoming wheelchair Large ears + + + + 15/17 (length cm) (7.1) (6-7) (6-8) bound in adulthood. Myelography in this Hypertelorism + + + + 19/19 patient showed what was described as (ICD cm) (3-5) (3-9) (3-5) Large hands + + + + 'questionable' spinal stenosis. Mohonen and Deep set nails + - + + 9/10 Menezes'9 reported a case ofWeaver syndrome Prominent finger/toe pads + - + + 6/9 Overriding toes + + + with instability of the cervical spine and specu- Syndactyly - + lated that this might explain progressive spas- Genital anomalies + + + Tone Normal Reduced Normal Reduced T10/18 ticity. Case 2 of the present series has fusion of 1 5/18 the second and third cervical vertebrae but no Reflexes Normal Brisk Brisk Brisk other axial anomaly. It is speculative whether progressive involvement of the spinal cord, on a background of 'central hypotonia', is the underlying cause of these lower limb signs.

Table 2 Comparative birth measurements in three overgrowth syndromes. ADDITIONAL FEATURES Weaver Sotos' Marshall" Weaver et al,' in their original paper, reported the presence of short penile in both Weight>97th entile 14/29 6/41 1/11 length > 90 cen their patients. This feature does not appear Weight<50th centile 3/29 4/41 6/11 to be a common finding in subsequent Length> 97th centile 15/18 23/27 5/10 > 90 cen cases, although cryptorchidism has been OFC> 97th centile 8/15 12/27 3/7 reported.I1216 Inguinal and umbilical herniae > 90 cen are common, the latter present in cases 2 and 3 *'Cut of' at 90th centile. of the current series. In addition, case 2 had a very high left testis and cases 1 and 3 had hydroceles in infancy. These deficits are now improving. At present, Hirsutism, which is more usually associated case 3 appears to be developing normally with MSS,5 has been reported by Jalaguier et (table 3). al4 in a patient where the diagnosis of either Speech in WSS is not only delayed, but is WSS syndrome or MSS syndrome is ques- also often described as slurred or dysarthric tioned. However, this feature has also been and the tone of the voice is rather hoarse and documented by Stoll et al'6 in a patient where low pitched. the diagnosis of WSS seems certain. Behavioural problems are common in WSS Other overgrowth syndromes such as Sotos and poor concentration and temper tantrums syndrome, Beckwith syndrome, and hemi- may be particularly difficult to manage. These hypertrophy have been associated with an problems are present in the three older chil- increased incidence of tumour formation.20 To dren in this report (cases 1, 2, and 4). It is date, only one case of a neuroblastoma has possible that these features reflect the patient's been reported in WSS syndrome.'9 frustration, particularly when communication Cardiac lesions have been recorded in four is a problem, rather than an intrinsic compon- out of nine patients in a review of WSS by ent of the syndrome. Similar behavioural Fitch.6 None is present in the four new problems have been recognised in children patients in this report. with Sotos syndrome.

Investigations NEUROLOGICAL FEATURES RADIOLOGICAL Tone appears to be altered in most cases and The bone age in all cases of WSS appears to be was described as increased in 10 out of 18, and advanced, although Stoll et al'6 reported a 6 decreased in five out of 18 by Ardinger et al.7 year old child with a normal bone age, but Hypotonia alone would obviously influence which had been significantly advanced at 18 early motor development and articulation. months of age. The bone age probably is dysharmonic, with the ossification of the carpal bones being more advanced than that seen Table 3 Early developmental milestones (months). in the phalangeal bones (table 4). However, it Case I Case 2 Case 3 Case 4 should be remembered that carpal assessments are highly variable and may Sitting unaided 9 9 7 9 not always be Walking unaided 17 17 14 20 accurate. First words - 13 16 22 Widened metaphyses, involving the femur 2 - word sentences 48 30 27 or humerus or both, were documented in three 336 Cole, Dennis, Hughes

of the present cases and in 16 out of 18 cases in a longer face and jaw compared to the rounder, the review by Ardinger et al.7 fuller face, retrognathia, and well defined, small, dimpled jaw of WSS. The facial gestalt currently perceived as typical for WSS may be ENDOCRINOLOGICAL age dependent and limited to the first couple of Endocrinological investigations to date have years of life. As our experience of WSS in been normal in most cases. 7912 Amir et al'4 adolescence and adulthood increases, it may described a case with acquired hypo- be that an 'older phenotype' becomes more thyroidism, but thyroid function tests are obvious. For example, the gestalt of case 1 (fig usually normal in WSS.'S"7 Stoll et al'6 lb) at the age of 1 year is very similar to the reported a low basal and stimulated level of appearance of the two original cases of WSS at human growth hormone (hGH) in a 6 year old a similar age.' However, the gestalt of case 1 at boy and his apparently affected mother, who the age of 5 years (fig Id) has clearly changed. also was found to have hyperprolactinaemia. Patients with Ruvalcaba-Myhre-Smith syn- However, normal hGH levels have been drome,24 like Sotos syndrome, also have rather reported by several authors and Amir et al'4 longer faces and can be further differentiated showed a normal 24 hour hGH pattern in the by the presence of pigmentation on the genit- patient they reported. alia, colonic polyps, and a positive family his- Although endocrinological abnormalities tory. have only been documented in three cases of The main diagnostic controversy is the dif- WSS, it is interesting to note that the same ferentiation of WSS from MSS. However, abnormalities, that is, hypothyroidism22 comparison of the phenotypes of these two and low basal and induced levels of hGH conditions shows that children with MSS have (Hindmarsh, personal communication), have much thinner faces and a rather gaunt appear- also been described occasionally in Sotos syn- ance accentuated by proptosis, anteverted drome. nares, small facial bones, and long, thin extremities. They also have poor weight gain, both pre- and postnatally, feeding difficulties CYTOGENETIC with aspiration, recurrent pneumonia, and Chromosomal analyses were reported in 12 out early death, usually within the first two years of the 29 cases included in this review and all of life. Both conditions are associated with a were normal. Only two patients (cases 1 and 2 significantly advanced bone age but character- in the present paper) appear to have had fragile istically MSS patients have broad middle pha- X studies; both were normal. langeal bones. This feature has also been described in the case who probably has WSS2 and therefore could be an occasional feature in Differential diagnosis Weaver syndrome. There are several conditions which may be Several authors2' have described families or associated with overgrowth and these are listed individual patients with features of both WSS in the differential diagnosis of WSS (table 5). and MSS and have suggested that the two However, most can be excluded by the absence syndromes are morphological variants of the of an advanced bone age and their differing same condition. This argument is addressed in facial phenotypes. The three conditions most some depth by Fitch.56 The present authors likely to cause confusion with WSS are are of the opinion that the two conditions are Sotos syndrome, Ruvalcaba-Myhre-Smith separate and that the cases of Bosch-Banyeras syndrome, and MSS. et at2 and Jalaguier et al4 are more typical of In Sotos syndrome, the infants are less likely WSS. The lack of postnatal overgrowth in the to have an increased birth weight and in child- former patient could be accounted for by the hood tend to be tall and thin.2' They also have documented but undefined 'cardiopathy'. The patient described by Shimura et al' is not typical of either WSS or MSS. The case Table 4 Bone age assessments (years). reported by Tsukahara et al25 as WSS has been Case 1 Case 2 Case 3 Case 4 reclassified by Stoll et al'6 as Simpson-Golabi- Behmel syndrome. The second patient with Chronological age 5-4 6-4 0-9 1-6 Tanner-Whitehouse suspected WSS described by Majewski et al9 is (TW2) bone age 8-2 8-8 1-9 2-0 believed by the authors to be more typical of Carpal bone age 11-6 9 4 4-4 2-6 benign familial macrocephaly, and this diagnosis ought to be considered within the differential diagnosis of WSS. Table S Differential diagnosis of Weaver-Smith syndrome. Sotos Marshall-Smith Inheritance Simpson-Golabi-Behmel In this review of 25 published cases and four Beckwith-Wiedemann Perlman new cases, nine are female and 20 are male. Proteus Most reports to date suggest sporadic occur- Sanfilippo Marfan rence of this condition, but there have been Neurofibromatosis type 1 three families where autosomal recessive in- Fragile X Klinefelter heritance has been postulated. In the family Trisomy 8 mosaicism described by Roussounis and Crawford,26 the Benign familial macrocephaly surviving sib has since been reviewed and Weaver syndrome 337

chromosome analysis showed the karyotype ears). It should be remembered that cases 46,XX, 5p-; the concurrence of this recognised reported at present probably lie at the more chromosomal syndrome and WSS would seem severe end of the spectrum. Without reviewing unlikely (R Mueller, personal communica- photographs of children at different ages, WSS tion). Teebi et al2' described a consanguineous may be difficult to differentiate from Sotos Bedouin family with two sibs manifesting syndrome. In the absence of a diagnostic features similar to those of WSS. However, on marker, the controversy regarding its separa- review of the clinical data, neither case would tion from MSS, and indeed Sotos syndrome, is appear to be typical of the syndrome. For likely to remain. Recurrence risks are still example, the younger sib does not exhibit unclear, but the majority of cases to date have accelerated growth and has delayed bone been isolated. maturation at the age of 13 months. Jalaguier et al4 reported two sibs with clinical features of The authors would like to thank Professor D both Weaver syndrome and Marshall-Smith Davies, Dr E Wozniak, and Dr C Millns for syndrome. Unfortunately, a photograph of the allowing us to report details of their patients older sib is not provided. Data on the surviv- and Professor G Roberts and J Ribeiro for ing sib are typical of Weaver-Smith syndrome. assessing the bone ages. Dr T R P Cole was Clinical data on the parents are insufficient to supported by an Action Research training fel- rule out mild expression of the WSS pheno- lowship when this work was undertaken. type. Therefore, either dominant or recessive 1 Weaver DA, Graham CB, Thomas IT, Smith DW. A new inheritance of Weaver syndrome might be overgrowth syndrome with accelerated skeletal matura- exhibited by this family, but this is impossible tion, unusual facies and camptodactyly. J Pediatr 1974;44:547-52. to confirm. 2 Bosch-Banyeras JM, Salcedo S, Lucaya J, Laverde R, There are a further three published pedi- Boronat M, Marti-Henneberg C. Acceleration du deve- loppement postnatal. Arch Fr Pediarr 1978;35:177-83. grees which are compatible with either autoso- 3 Shimura T, Utsumi Y, Fujikawa S., Nakamura H, Baba K. mal dominant inheritance with sex limited Marshall-Smith syndrome with large bifrontal diameter, broad distal femora, camptodactyly and without broad expression or X linked recessive inheritance. middle phalanges. J Pediatr 1979;94:93-5. As previously stated, patient 2 described by 4 Jalaguier J, Montoya F, Germain M, Bonnet H. Avance de la maturation osseuse et syndrome dysmorphique chez Majewski et al9 was felt by the authors possibly deux germains. J Genet Hum 1983;5:385-95. to be more typical of benign familial macroce- 5 Fitch N. The syndromes of Marshall and Weaver. J Med Genet 1980;17:174-8. phaly. The other two families are described by 6 Fitch N. Update on the Marshall-Smith-Weaver con- Ardinger et al7 (case 1) and Stoll et al.'6 In both troversy. Am J Med Genet 1985;20:559-62. 7 Ardinger HH, Hanson JW, Harrod MJE, et al. Further these reports, it is not possible on the informa- delineation of Weaver syndrome. 7 Pediatr 1986; tion provided to confirm or refute the sugges- 2:228-35. 8 Cole TRP, Hughes HE. Sotos syndrome. Part 1. A study of tion that the two mothers show a mild expres- the diagnostic criteria and natural history. Am J Med sion of WSS while their affected sons show the Genet (submitted). 9 Majewski F, Ranke M, Kemperdick H, Schmidt E. The full clinical picture. Weaver syndrome: a rare type of primordial overgrowth. EurT.7Pediatr 1981;137:277-82. 10 Moreno HD, Kirkland R. Another candidate for the overgrowth syndrome. J Pediatr 1974;85:583. 11 Gemme G, Bonioli E, Ruffa G, Lagorio V. The Weaver Natural history syndrome. J7 Pediatr 1980;97:962-4. It is difficult to assess the risk of early child- 12 Weisswichert PH, Knapp G, Wilich E. Accelerated bone maturation syndrome of the Weaver type. Eur I Pediatr hood mortality in WSS while the controversy 1981;137:329. concerning separation of WSS and MSS 13 Meinecke P, Schaefer E, Engelbrecht R. The Weaver syndrome in a girl. Eur I Pediatr 1983;141:58. remains. The two patients described by 14 Amir N, Gros-Kieselstein E, Hirsch HJ, et al. Weaver- Jalaguier et al4 died in infancy and the authors Smith syndrome: a case study with long term follow up. Am J Dis Child 1984;183:1113-7. believe that at least the second sib had WSS. 15 Farrell SA, Hughes HE. Brief clinical report: Weaver Beyond early childhood years, life expectancy syndrome with pes cavus. Am J Med Genet 1985; 21:737-9. is probably normal, at least into early adult- 16 Stoll C, Talon P, Mengus L, Roth M, Dott B. A Weaver- hood. Little else is known about the natural like syndrome with endocrinological abnormalities in a boy and his mother. Clin Genet 1985;28:255-9. history of Weaver syndrome as only two adults 17 Thompson EM, Hill S, Leonard JV, et al. A girl with have been fully documented.718 Both were tall Weaver syndrome. .7 Med Genet 1987;24:232-4. with adult + 18 Greenberg F, Wasiewski W, McCabe ERB. Brief clinical heights 5 2 SD and + 3 5 SD. report: Weaver syndrome: the changing phenotype in an Therefore, it is possible that final height in adult. Am I Med Genet 1989;33:127-9. WSS may be greater than in other overgrowth 19 Muhonen MG, Menezes AH. Weaver syndrome and instability of the upper cervical spine. I Pediatr 1990; syndromes. The facial characteristics appear to 116:596-9. 20 Cohen MM. A comprehensive and critical assessment of change markedly through childhood and ado- overgrowth and overgrowth syndromes. Adv Hum Genet lescence."8 There was no evidence of intellec- 1989;18:181-303. 21 Rutter S, Cole TRP. Psychological study of Sotos syn- tual regression in any of the reported cases. drome. Dev Med Child Neurol 1991;33:898-905. 22 Hulse JA. Two children with cerebral gigantism and con- genital hypothyroidism. Dev Med Child Neurol 1981; 23:242-6. Conclusions 23 Cole TRP, Hughes HE. The diagnostic features and natural history of Sotos syndrome. J Med Genet 1990;27:646A. Weaver-Smith syndrome is a rare overgrowth 24 Ruvalcaba RHA, Myhre S, Smith DW. A syndrome with macrencephaly, intestinal polyps and pigmentary penile syndrome identified by the presence of ad- lesions. Clin Genet 1980;18:413. vanced bone age, metaphyseal flaring of the 25 Tsukahara M, Tanaka S, Kalii T. A Weaver like syndrome and in a Japanese boy. Clin Genet 1984;25:73-5. long bones, developmental delay, charac- 26 Roussounis SH, Crawford MJ. Siblings with Weaver syn- teristic facies (macrocephaly, broad forehead, a drome. I7 Pediatr 1983;102:595-7. rounded face in 27 Teebi AS, Sundareshan TS, Hammouri MY, et al. A new infancy, long, prominent phil- autosomal recessive disorder resembling Weaver syn- trum, small but distinctive chin, and large drome. Am 7Med Genet1989;33:479-82.